DESCRIPTION: (Applicant's Description) The principal aims for the 04-07 years of AI-42010 are: (A) To enhance the potency of our 3,5-linked (nitrogen displaced) pyrrolinone FIIV-1 protease inhibitors via (1) optimization of the Asp29 (N-H)/inhibitor (carbamate C=O) hydrogen-bond and (2) improvement of the binding interaction at the S2 binding pocket; (B) To design and synthesize a second-generation HIV-1 protease inhibitor based on the 2,5-linked (carbonyl displaced) pyrrolinone scaffold which incorporates a carbamate moiety at P2; (C) To improve the potency of our MMP inhibitors by increasing the size and length of the P1' side-chains; and (D) To design and synthesize a series of 3,5-linked pyrrolinone inhibitors for the enzyme glutathione S-transferase. The availability of our newly developed solid-support pyrrolinone chemistry will significantly augment these efforts (vide infra). To support the demand for varied 3,5-linked pyrrolinones, we will also (E) extend our 3-step iterative solid-support synthetic method to a more efficient 2-step protocol employing unsaturated a-aminolactones. This synthetic venture will require (F) the development an effective synthesis of the requisite unsaturated a-aminolactone building blocks possessing both coded or non-coded amino acid side chains. We will then (G) elaborate focused libraries aimed at the discovery of improved MMP enzyme inhibitors. In the 2,5-linked polypyrrolinone area, we will develop (H) a convergent synthetic protocol. To define the solution conformational features of the (nitrogen displaced) polypyrrolinone scaffold, we will (I) perform both aggregation and spectroscopic studies on a series of 3,5-linked polypyrrolinones. Finally, we will (J) complete the synthesis of a 3,5-linked tetrapyrrolinone beta-turn mimetic, (K) test its biological activity at the somatostatin receptor, and (L) incorporate a 3,5-linked trispyrrolinone onto a dodecapeptide sequence to explore the use of the nitrogen displaced pyrrolinone motif to mimic helical structures in peptides.